Piperidine skeletons

A method for regioselective introduction of a bis(methoxycarbonyl)-methyl group into the 4-position of the piperidine skeleton was explored, and this method was applied to the preparation of cis- and rra j-2,4-disubstituted piperidines (e.g., 114) starting from 2-piperidinecarboxylic acid <96TL(37)5715>. 

Treatment of an w-acylaminal derivative 83 with allylsilanes in the presence of a Lewis acid or a Brpnsted acid gives the corresponding condensation products (equation 55)122-125. The reaction can also proceed intramolecularly, e.g. in the formation of 84 and 85 (equations 56 and 57). A piperidine skeleton 86 can also be formed by such intramolecular cyclization (equation 58)126. 

Piperidine skeletons are easily prepared by utilizing a unique [3 + 3]-type annela-tion between allyltrimethylsilane and a,oc -dimethoxylated amides which are easily... 

Tetrahydrofuran, tetrahydropyran, pyrrolidine, and piperidine skeletons can be constructed by these reactions. 

Heating or photolytic treatment of A,A-dialkyl-A-haloamine in sulfuric acid or trifluoroacetic acid, followed by neutralization with a base, generates a pyrrolidine or piperidine skeleton. This is the Hofmann-Loffler-Frey tag reaction, and the reaction comprises of the formation of an electrophilic aminium radical, 1,5-H shift (6-membered transition state) or 1,6-H shift (7-membered transition state), formation of 4-haloalkyl ammonium or 5-haloalkyl ammonium, and its polar cyclization by neutralization with a base. Eq. 6.16 shows the formation of A-alkyl pyrrolidine (31) from A-chloro-A-alkyl-A-butylamine (30) in sulfuric acid [46, 47]. 

The biomimetic construction of piperidine skeletons from N-methylhomoallyl-amines is performed by means of the ruthenium-catalyzed oxidation and subsequent olefm-iminium ion cyclization reaction. trans-l-Phenyl-3-propyl-4-chloropiper-idine 57 ivas obtained from N-methyl-N-(3-heptenyl)aniline stereoselectively via 56 upon treatment ivith a 2 N HCI solution (Eq. 3.72). This cyclization is the first demonstration of biomimetic formation of piperidine structure using N-methyl group, and can be rationalized by assuming the formation of iminium ion 58 by protonation of the oxidation product 56, subsequent elimination of f-BuOOH, nucleophilic attack of an alkene, giving a carbonium ion, which is trapped with Cl nucleophile from the less hindered side. 

Arecoline is thought to be derived with nicotinic acid (niacin) as a precursor (Section 10.1). On the other hand, coniine, a toxic alkaloid of Conium maculatum (Apiaceae) and also possessing the piperidine skeleton, is biosynthesized through the polyketide pathway, which is completely different from that of arecoline. Coniine will be discussed in Chapter 15. 

Later, the group reported a highly enantioselective construction of 5- and 7-lactone[2,3-fc]piperidine skeletons by a tandem aza-Diels-Alder-hemiacetal formation-oxidation process from A-tos-l-aza-1,3-butadienes 88 and aliphatic dialdehydes 90, Scheme 3.32 [47]. 

Scheme 3.32 Enantioselective construction of lactone[2,3-f>]piperidine skeletons via oiganocata-lytic tandem aza-Diels-Alder-hemiacetal formation-oxidation process...

At the same time, there are alkaloids of piperidine skeleton which are derived from acetic acid or nicotinic acid pathways, e.g., coniine Conium maculatum) or arecoline (Areca catechu) and anatabine Nicotiana tabacum,... 

The typical alkaloids of the family Lobeliaceae have a piperidine skeleton. There are alkaloid bases disubstituted in the a, aj-position (i.e., in C2 and Cg) and those monosubstituted in the a-position (C2) (Figs. 11.23, 11.24] [36]. 

Under Lewis acidic conditions, the silyl bromide (1) and a, -dimethoxylated amides undergo a [3 + 3] type annulation which is useful for the construction of the piperidine skeleton (eq 13). 7 xfjg silyl bromide (1) is also an excellent reagent for the stereoselective introduction of a functionalized allyl group at the anomeric center of the glucosides (eq 14). ... 

SCHEME 11.5 The biosynthetic route toward the piperidine skeleton found in lysine alkaloids. 

When using aliphatic aldehydes tethered to arene motifs as substrates, an enan-tioselective sequential aza-hetero-Diels-Alder and Friedel-Crafts reaction was successfully achieved by the same group [63]. Similarly, optically active lactone[3,3-b] piperidine skeletons 140 can be obtained by tandem aza-hetero-Diels-Alder reaction-hemiacetal formation-oxidation from a,P-unsaturated imines 136 and glutaraldehyde (139) (Scheme 38.41) [64]. Enamine catalysis of the inverse-electron-demand aza-hetero-Diels-Alder reaction was further extended to o-benzoquinone diimide 141 by Chen s group [65]. Various hydroquinoxalinones 142 can be obtained in high yields with excellent enantioselectivities (Scheme 38.42). 

The aza Diels-Alder cycloaddition of 1-azadienes 139 with alkenes 138 also lead to the synthesis of piperidines skeletons 140 with the creation of three stereogenic centers (Scheme 41.30). If the N-1 position is substituted with an electron donating group, the 1-azadiene react with electron poor dienophiles in a normal electron demand Diels-Alder reaction. However, an electron-withdrawing group at N-1, allowed for the inverse electron demand Diels-Alder cycloaddition to occur with electron-rich dienophiles. ... 

Among the new structures it is worth mentioning halidonin A, isolated from a Korean Halidona sp. with a new carbon skeleton neopetrosiamine A from the Caribbean Neopetrosia proxima with a new tetracydic bis-piperidine skeleton and three new alkaloids related to halidonacydamine, but isolated from an Indonesian Halichondrid sponge of the genus Halichondria. 

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